Difelikefalin

Difelikefalin has not been studied in subjects with severe hepatic impairment (National Cancer Institute (NCI) Organ Dysfunction Working Group (ODWG)) and is therefore not recommended for use in this patient population.

Concurrent administration of medicinal products such as sedating antihistamines, opioid analgesics or other CNS depressants (e.g., clonidine, ondansetron, gabapentin, pregabalin, zolpidem, alprazolam, sertraline, trazodone) may increase the likelihood of dizziness and somnolence.

Difelikefalin is a peripherally acting kappa opioid receptor agonist with restricted access to the central nervous system (CNS). The blood-brain barrier (BBB) integrity is important for minimizing difelikefalin uptake into the CNS. Patients with clinically important disruptions to the BBB (e.g., primary brain malignancies, CNS metastases or other inflammatory conditions, active multiple sclerosis, advanced Alzheimer’s disease) may be at risk for difelikefalin entry into the CNS. Difelikefalin should be prescribed with caution in such patients taking into account their individual benefit-risk balance with observation for potential CNS effects.

There are no or limited amount of data from the use of difelikefalin in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

As a precautionary measure, it is preferable to avoid the use of difelikefalin during pregnancy.

It is unknown whether difelikefalin is excreted in human breast milk.

A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from difelikefalin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Animal studies have shown excretion of difelikefalin in breast milk.

Fertility

There are no data on the effect of difelikefalin on fertility in humans. In rat studies with difelikefalin, there was no effect on fertility.

Difelikefalin has minor influence on the ability to drive and use machines. Somnolence and/or dizziness have been reported in patients receiving difelikefalin. Patients should be cautioned about driving or operating hazardous machinery until the effect of difelikefalin on the patient’s ability to drive or operate machinery is known. Somnolence occurred within the first 3 weeks of treatment and tended to subside with continued dosing. Dizziness occurred within the first 9 weeks of treatment and was generally transient.

Summary of the safety profile

In placebo controlled and uncontrolled phase 3 clinical studies, approximately 6.6% of the patients experienced at least one adverse reaction during difelikefalin treatment. The most common adverse reactions were somnolence (1.1%), dizziness (0.9%), paraesthesia (including hypoesthesia, paraesthesia oral and hypoesthesia oral) (1.1%), headache (0.6%), nausea (0.7%), vomiting (0.7%), diarrhoea (0.2%) and mental status changes (including confusional state) (0.3%). Most of these events were mild or moderate in severity, did not lead to deleterious consequences, and resolved with ongoing therapy. No event was serious and the incidence of events leading to treatment discontinuation was ≤0.5% for any of the adverse reactions listed above.

Tabulated list of adverse reactions

The adverse reactions observed in the placebo-controlled and uncontrolled phase 3 clinical studies in patients (N=1306) treated with difelikefalin are listed in the table below by MedDRA system organ class, preferred term and frequency. The frequency is classified as common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions attributed to the treatment with difelikefalin in haemodialysis patients:

¹ Mental status changes included MedDRA preferred terms of confusional state and mental status changes.
² Paraesthesia included MedDRA preferred terms of paraesthesia, hypoesthesia, paraesthesia oral and hypoesthesia oral.

Description of selected adverse reactions

Somnolence

Somnolence was reported as treatment emergent adverse event in 2.2% of subjects randomised to difelikefalin. The vast majority of these events was mild or moderate in severity. In 0.3% of patients, somnolence led to discontinuation of treatment with difelikefalin. Somnolence was reported as serious adverse event in <0.1% of difelikefalin treated subjects. In 1.1% of patients, somnolence was reported to have a causal relationship to difelikefalin treatment. Somnolence occurred within the first 3 weeks of treatment and tended to subside with continued dosing. The likelihood of somnolence may increase when difelikefalin is concomitantly used with other medicinal products.

Dizziness

Dizziness was reported as treatment emergent adverse event in 7.9% of subjects randomised to difelikefalin. The vast majority of these events was mild or moderate in severity. In 0.5% of patients, dizziness led to discontinuation of treatment with difelikefalin. Dizziness was reported as serious adverse event in 0.5% of difelikefalin treated subjects. In 0.9% of patients, dizziness was reported to have a causal relationship to difelikefalin treatment. Dizziness occurred within the first 9 weeks of treatment and was generally transient.

The likelihood of dizziness may increase when difelikefalin is concomitantly used with other medicinal products.

Mental status changes

Mental status change (including confusional state) was reported as treatment emergent adverse event in 4.4% of subjects randomised to difelikefalin.

The majority of these events was mild or moderate in severity. In less than 0.2% of patients, mental status changes led to discontinuation of treatment with difelikefalin.

Mental status changes were reported as serious adverse event in 2.2% of difelikefalin treated subjects. In 0.3% of patients, mental status changes were reported to have a causal relationship to difelikefalin treatment.